The present invention is directed to a process for producing 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one. In particular, the present invention is directed to an enantioselective process for producing the same.
xcex4-Lactones, including pyranones such as 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-ones are useful intermediates in the preparation of a variety of fine chemicals and pharmaceutically active compounds. For example, 3-hexyl-4-hydroxy-6-undecyl-5,6-dihydro-pyran-2-one is a well known precursor for the preparation of oxetanones such as tetrahydrolipstatin. See for example, U.S. Pat. Nos. 5,245,056 and 5,399,720, both issued to Karpf et al.; and U.S. Pat. Nos. 5,274,143 and 5,420,305, both issued to Ramig et al.
One method of preparing 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-ones such as 3-hexyl-4-hydroxy-6-undecyl-5,6-dihydro-pyran-2-one involves intramolecular cyclization of xcex1-haloesters, typically (xcex1-bromoesters, using a metal as a reducing agent. Broadly, this type of reaction is generally known as an intramolecular Reformatsky reaction. For example, the above mentioned U.S. Pat. Nos. 5,274,143 and 5,420,305, both issued to Ramig et al. disclose intramolecular Reformatsky using a xe2x80x9clow valent metalxe2x80x9d such as zinc, Li, Na, K and the like including amalgams of Zn such as Zn(Cu) and Zn(Ag).
While a variety of metals may be used in the Reformatsky reaction, it is generally believed and widely accepted that some metals such as magnesium cannot be generally used in the Reformatsky reaction. See for example, Advanced Organic Chemistry, 3rd ed., March, J., John Wiley and Sons, New York, N.Y., 1985, pp. 822-824. However, the use of magnesium is more desirable than zinc in industrial processes, because the magnesium waste can be more easily disposed of and is less hazardous to the environment than the zinc waste. Moreover, many Reformatsky reactions, including those disclosed in U.S. Pat. Nos. 5,274,143 and 5,420,305, use ether as a solvent (see Examples 5, 10 and 12), which has a low boiling point, i.e., less than 40xc2x0 C., which may result in a high concentration of solvent vapor within the production facility, thereby creating a potentially hazardous condition, especially in large scale production facilities.
Other methods of preparing tetrahydrolipstatin use a xcex2-hydroxy ester, e.g., methyl 3-hydroxy tetradecanoate, as an intermediate. See for example, Pommier et al., Synthesis, 1994, 1294-1300, Case-Green et al., Synlett., 1991, 781-782, Schmid et al., Proceedings of the Chiral Europe""94 Symposium, Sep. 19-20, 1994, Nice, France, and the above mentioned U.S. Patents. Some methods of preparing oxetanones, such as those disclosed in the above mentioned U.S. Patents issued to Karpf et al., use a xcex2-hydroxy ester as an intermediate to prepare the xcex4-lactone which is then used in the synthesis of oxetanones.
The stereochemistry of a molecule is important in many of the properties of the molecule. For example, it is well known that physiological properties of drugs having one or more chiral centers, i.e., stereochemical centers, may depend on the stereochemistry of a drug""s chiral center. Thus, it is advantageous to be able to control the stereochemistry of a chemical reaction.
Many oxetanones, e.g., tetrahydrolipstatin, contain one or more chiral centers. Intermediates such as xcex4-lactones and xcex2-hydroxy esters in the synthesis of tetrahydrolipstatin contain one chiral center. Some syntheses of these intermediates, such as those disclosed in the above mentioned U.S. Patents issued to Karpf et al., are directed to preparation of a racemic mixture which is then resolved at a later stage to isolate the desired isomer. Other methods are directed to an asymmetric synthesis of the xcex2-hydroxy ester by enantioselectively reducing the corresponding xcex2-ketoester.
Moreover, in order to achieve a high yield of the desired product, some current asymmetric hydrogenation processes for reducing methyl 3-oxo-tetradecanoate require extremely pure reactants, e.g., hydrogen gas purity of at least 99.99%, thus further increasing the cost of producing the corresponding xcex2-hydroxy ester.
Therefore, there is a need for a process for producing xcex4-lactones which does not require zinc based Reformatsky-type reactions. There is also a need for enantioselective reduction of xcex2-ketoesters under conditions which do not require extremely pure reactants or high hydrogen gas pressure.
One embodiment of the present invention provides a process for the preparation of a xcex4-lactone of the formula: 
comprising contacting an xcex1-halo ester of the formula: 
with a reactive species generating reagent selected from the group consisting of Grignard reagents, magnesium, magnesium-sodium mixtures, samarium, manganese, and mixtures thereof under conditions sufficient to produce said xcex4-lactone, where R1 is C1-C20 alkyl; R2 is H or C1-C10 alkyl; Y is a halide; and Z is nitrile, ester, amide, hydroxyamino amide, acid halide, anhydride, carboxyl carbonate or carboxyl haloformate.
Another embodiment of the present invention provides a process for producing (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one comprising contacting an xcex1-bromo ester of the formula: 
with a reactive species generating reagent described above under conditions sufficient to produce (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one, where Z is nitrile or a moiety of the formula xe2x80x94C(xe2x95x90O)W; W is C1-C6 alkoxide, C6-C20 aryloxide, C7-C20 arylalkoxide, halide, C1-C6 carboxylate or a moiety of the formula xe2x80x94NR3R4; and each of R3 and R4 is independently C1-C6 alkyl, C6-C20 aryl, C7-C20 arylalkyl, C1-C6 alkoxide, C6-C20 C7-C20 arylalkoxide or R3 and R4 together form a moiety of the formula xe2x80x94(CR5R6)axe2x80x94Qxe2x80x94(CR7R8)bxe2x80x94; each of R5, R6, R7 and R8 is independently H or C1-C6 alkyl, C6-C20 aryl, C7-C20 arylalkyl; Q is O, NR9 or S; R9 is H, an amine protecting group, C1-C6 alkyl, C6-C20 aryl or C7-C20 arylalkyl; and each of a and b is independently an integer from 1 to 4.
Yet another embodiment of the present invention provides a compound of the formula: 
or its corresponding enolate of the formula: 
where R1 is C1-C20 alkyl; R2 is H or C1-C10 alkyl; X is a halide; and Z is nitrile, ester, amide, hydroxyamino amide, acid halide, anhydride, carboxyl carbonate or carboxyl haloformate. A particularly preferred compound of the present invention is of the formula: 
or its corresponding enolate of the formula: 
Preferably, Z is an ester. More preferably Z is a moiety of the formula xe2x80x94C(xe2x95x90O)OMe or xe2x80x94C(xe2x95x90Ot-Bu.
Still yet another embodiment of the present invention provides a process for producing xcex2-ketoester of the formula: 
comprising:
(a) contacting an alkyl acetoacetate of the formula CH3C(xe2x95x90O)CH2C(xe2x95x90O)OR10, with a magnesium alkoxide, preferably magnesium methoxide, under conditions sufficient to produce a magnesium salt of said alkyl acetoacetate and a first alcohol, preferably methanol, and removing at least a portion of said first alcohol;
(b) contacting said alkyl acetoacetate magnesium salt with an alkyl acyl halide of the formula R1C(xe2x95x90O)X, preferably lauroyl chloride, under conditions sufficient to produce a tricarbonyl compound of the formula R1C(xe2x95x90O)CH[C(xe2x95x90O)CH3]C(xe2x95x90O)OR10; and
(c) contacting said tricarbonyl compound with a second alcohol, preferably methanol, under conditions sufficient to produce said xcex2-ketoester, wherein
X is a halide, preferably chloride;
R1 is C1-C20 alkyl, preferably undecyl; and
R10 is C1-C6 alkyl, C6-C20 aryl or C7-C20 arylalkyl, preferably methyl.
Preferably, the reaction is carried out in a non-polar organic solvent, more preferably a solvent that forms an azeotrope with the alcohol that is generated in the reaction mixture, and most preferably toluene.
The reaction temperature of the step (a) is at least about 40xc2x0 C., preferably at least about 45xc2x0 C.
The reaction temperature of the step (b) is at least about 50xc2x0 C., preferably at least about 60xc2x0 C.
The reaction temperature of the step (c) is at least about 70xc2x0 C., preferably at least about 75xc2x0 C.
Preferably, the step (c) is carried without adding any acid or base.
As used herein, the term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ccontactingxe2x80x9d or xe2x80x9creactingxe2x80x9d refers to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
The term xe2x80x9calkylxe2x80x9d refers to aliphatic hydrocarbons which can be straight or branched chain groups. Alkyl groups optionally can be substituted with one or more substituents, such as a halogen, alkenyl, alkynyl, aryl, hydroxy, amino, thio, alkoxy, carboxy, oxo or cycloalkyl. There may be optionally inserted along the alkyl group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms. Exemplary alkyl groups include methyl, ethyl, i-propyl, n-butyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, trichloromethyl, pentyl, hexyl, heptyl, octyl, decyl and undecyl.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic carbocyclic or heterocyclic aromatic ring moieties. Aryl groups can be substituted with one or more substituents, such as a halogen, alkenyl, alkyl, alkynyl, hydroxy, amino, thio, alkoxy or cycloalkyl. Exemplary aryl groups include phenyl, toluyl, pyrrolyl, thiophenyl, furanyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl.
The present invention provides a process for the preparation of xcex4-lactones, including pyranones, such as 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-ones. In particular, the present invention provides a process for the preparation of a xcex4-lactone of the formula: 
where R1 is C1-C20 alkyl, preferably undecyl; and R2 is H or C1-C10 alkyl, preferably hexyl. The present invention also provides a process for enantioselectively producing the xcex4-lactone I. In one embodiment of the present invention, the enantioselective process provides (6R)-xcex4-lactone I, i.e., a compound of the formula: 
It should be appreciated that the xcex4-lactone of formula I and the corresponding enantiomerically enriched xcex4-lactone IA may also exist in, or are in equilibrium with, their tautomeric forms: 
and 
respectively. Therefore, any reference to the xcex4-lactone of formula I or IA implicitly includes its tautomeric form of formula II or IIA, respectively.
The present invention will now be described in reference to the syntheses of enantiomerically enriched xcex4-lactone IA. It should be appreciated that the racemic form of xcex4-lactone I or xcex4-lactones having the opposite stereochemical configuration as that of formula IA, while not explicitly discussed herein, can be readily prepared using the processes of the present invention by using a racemic mixture or opposite stereochemically configured starting materials, respectively.
One embodiment of the present invention provides a process for preparing the xcex4-lactone IA by treating an (R)-(xcex1-halo ester of the formula: 
with a reactive species generating reagent selected from the group consisting of Grignard reagents, magnesium, magnesium-sodium mixtures, samarium, manganese, and mixtures thereof under conditions sufficient to produce the xcex4-lactone IA, where R1 and R2 are as described above; Y is a halide, preferably bromide; and Z is nitrile (xe2x80x94CN) or a moiety of the formula xe2x80x94C(xe2x95x90O)W; where W is C1-C6 alkoxide, C6-C20 aryloxide, C7-C20 arylalkoxide, halide, C1-C6 carboxylate (i.e., xe2x80x94OC(xe2x95x90O)Rxe2x80x2, where Rxe2x80x2 is H or C1-C5 alkyl), haloformate (i.e., xe2x80x94OC(xe2x95x90O)Y1, where Y1 is a halide) or a moiety of the formula xe2x80x94NR3R4, where each of R3 and R4 is independently C1-C6 alkyl, C6-C20 aryl, C7-C20 arylalkyl, C1-C6 alkoxide, C6-C20 aryloxide, C7-C20 arylalkoxide or R3 and R4 together form a cyclic moiety of the formula xe2x80x94(CR5R6)axe2x80x94Qxe2x80x94(CR7R8)bxe2x80x94, where each of R5, R6, R7 and R8 is independently H or C1-C6 alkyl, C6-C20 aryl, C7-C20 arylalkyl; Q is O, NR9 or S; R9 is H, an amine protecting group, C1-C6 alkyl, C6-C20 aryl or C7-C20 arylalkyl; and each of a and b is independently an integer from 1 to 4. A variety of amine protecting groups are known in the art, and can be employed. Examples of many of the possible amine protecting groups can be found in Protective Groups in Organic Synthesis, 3rd edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, New York, 1999, which is incorporated herein by reference in its entirety.
As used herein, the term xe2x80x9creactive species generating reagentxe2x80x9d refers to a reagent or a compound which generates a reactive intermediate species from an xcex1-halo ester compound III which can undergo an intramolecular cyclization reaction to produce the xcex4-lactone I. Preferably, the reactive species generating reagent is a Grignard reagent or magnesium metal. More preferably, the reactive species generating reagent is a Grignard reagent.
Preferably, Z is selected from the group consisting of morpholino amide (i.e., xe2x80x94C(xe2x95x90O)W, where W is morpholine moiety), N,O-dimethylhydroxylamino amide (i.e., xe2x80x94C(xe2x95x90O)W, where W is xe2x80x94N(CH3)(OCH3), nitrile (i.e., xe2x80x94CN), acid chloride (i.e., xe2x80x94C(xe2x95x90O)Cl), pivaloyl anhydride (i.e., xe2x80x94C(xe2x95x90O)W, where W is xe2x80x94OC(xe2x95x90O)t-Bu), methyl ester, ethyl ester and t-butyl ester.
It is widely held and accepted that in general Grignard species cannot be formed from xcex1-halo esters. See Advanced Organic Chemistry, 3rd ed., March, J., John Wiley and Sons, New York, N.Y., 1985, 822-824. But see, Org. Synthesis, 1973, 53, 1882; Kelly, Tet. Lett., 1985, 26, 2173-2176; and MMJ, J Amer. Chem. Soc., 1990, 112, 7659-7672. However, surprisingly and unexpectedly, the present inventors have found that treating an (xcex1-halo ester III with magnesium produces the xcex4-lactone IA. Without being bound by any theory, it is believed that adding magnesium metal to xcex1-halo ester III results in initial formation of an intermediate, xcex1-magnesium halide ester species, which undergoes the intramolecular cyclization reaction. Furthermore, it is believed that addition of a Grignard reagent to xcex1-halo ester III results in a metal-halide exchange reaction again forming an xcex1-magnesium halide ester species, which undergoes an intramolecular cyclization reaction to produce the xcex4-lactone IA.
Typically, the reaction is carried out in an aprotic organic solvent such as tetrahydrofuran (THF), n-butyl ether, dimethoxy ethane (DME), methyl t-butyl ether (MTBE), toluene, 2-methyltetrahydrofuran or the like, preferably under an inert atmosphere such as nitrogen, argon, helium or the like.
An intramolecular cyclization reaction which forms the xcex4-lactone IA can be favored over intermolecular reaction by having a relatively low concentration of the xcex1-halo ester III. Preferably, the concentration of xcex1-halo ester III is about 2.5 M or less, more preferably about 2.0 M or less, and most preferably about 1.5 M or less.
The reaction temperature is generally from about 40xc2x0 C. to about 65xc2x0 C. However, the reaction temperature depends on a variety of factors such as the solvent used and the presence or absence of one or more additives in the reaction mixture, which is discussed in detail below.
One particular aspect of the present invention provides a process for producing xcex4-lactone IA by treating the xcex1-halo ester III with a Grignard reagent. Without being bound by any theory, it is believed that addition of a Grignard reagent to the xcex1-halo ester III results in a metal-halide exchange to produce a reactive species, e.g., xcex1-magnesium halide ester, which undergoes an intramolecular cyclization reaction to produce the cyclized product xcex4-lactone IA. When a Grignard reagent is used as a reactive species generating agent in equal to or less than stoichiometric amount relative to the xcex1-halo ester III, it is believed that the initially formed cyclized intermediate, which collapses to form the magnesium organometallic species of Compound I and methanol (where Z is xe2x80x94COOMe), reacts with the basic xcex1-magnesium halide ester or the added Grignard reagent which may be present in the reaction mixture, thereby resulting in a relatively low yield of the xcex4-lactone IA.
The yield of the xcex4-lactone IA can be increased significantly by adding an excess amount of the Grignard reagent. In this manner, the excess Grignard reagent is used to quench, i.e., deprotonate, compounds deriving from the collapse of the initially formed cyclized intermediate or any other compounds which contain an acidic proton. Thus, preferably the amount of Grignard reagent added is from about 2 to about 10 equivalents, more preferably from about 2 to about 5 equivalents, still more preferably from about 3 to about 5 equivalents, and most preferably about 3 equivalents.
Any Grignard reagent can be used in the present invention including a variety of substituted and unsubstituted aryl and alkyl Grignard reagents including methyl, ethyl, isopropyl, butyl, sec-butyl, tert-butyl, 2-methoxyphenyl, t-amyl, t-octyl, hexyl, pentyl, and 1-octyl magnesium halides, such as magnesium bromides and magnesium chlorides. Preferred Grignard reagents include tert-butyl magnesium chloride and tert-butyl magnesium bromide. A more preferred Grignard reagent is tert-butyl magnesium chloride.
While the xcex1-halo ester III and the reactive species generating reagent can be combined or added in any sequence, it has been found that when the reactive species generating reagent is a Grignard reagent a simultaneous addition of the xcex1-halo ester III and the Grignard reagent is particularly preferred. For example, simultaneous addition of 13.6 mL solution of 30.7 mmol of methyl (3R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoate in tetrahydro-furan (THF) and 3 equivalents of tert-butyl magnesium chloride in 86 mL of THF over a one hour period to a 60xc2x0 C. reaction vessel containing about 10 mL of THF solvent resulted in 97% yield (A.N., i.e., area normalized) of (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one when the crude product was analyzed by a gas chromatography 1 hr after the complete addition of reagents.
Processes of the present invention can also include the step of adding an additive selected from the group consisting of trapping agents, metal activators, Lewis acid rate enhancers, and mixtures thereof.
As used herein, the term xe2x80x9ctrapping agentxe2x80x9d refer to a compound which can prevent internal proton quench of the reactive species generating reagent, e.g., a Grignard reagent, or the in situ generated reactive intermediate species, e.g., xcex1-magnesium halide ester. Exemplary trapping agents include amines such as triethylamine, diisopropylethylamine, tributyl-amine, and 2,2,6,6-tetramethylpiperidine, which form amine hydrohalides;, anhydrides and acyl chlorides, which can react with the initially formed intramolecular cyclization product to form enol esters; halocarbonates, including chloroformates such as methyl chloroformate and benzyl chloroformate, which can react with the initially formed intramolecular cyclization product to form enol carbonates; and silylating agents such as silyl chlorides, including trimethylsilyl chloride, tert-butydimethylsilyl chloride, and triisopropylsilyl chloride, and hexamethyldisilazane, which can react with the initially formed intramolecular cyclization product to form silyl enol ethers. When a trapping agent such as an anhydride, an acyl chloride, a halocarbonate, or a silylating agent is present, the resulting intermediate product (e.g., an enol ester, an enol carbonate, or a silyl enol ether, respectively) may be isolated and/or purified before producing the desired xcex4-lactone I. The isolated and/or purified intermediate product can be readily converted into the desired xcex4-lactone I by deprotection of the enol ester, the enol carbonate, or the silyl enol ether. Such deprotection reactions are well known to one of ordinary skill in the art.
The term xe2x80x9cmetal activatorxe2x80x9d refers to a compound which activates a metal (i.e., magnesium, magnesium-sodium mixtures, samarium, manganese, or mixtures thereof) in the formation of a reactive intermediate species. Exemplary metal activators include 1,2-dibromoethane; 1-bromo-2-chloroethane; anthracene; iodine; other metals, such as sodium; metal salts, such as zinc chloride, magnesium chloride, magnesium bromide, magnesium iodide, and iron salts including iron bromides, iron cyclopentadienes; and mixtures thereof. Preferably, the metal activator is selected from the group consisting of 1,2-dibromoethane, iodine, sodium, zinc chloride, iron bromides (e.g., ferric bromide), magnesium chloride, magnesium bromide, magnesium iodide, and mixtures thereof. The metal can be pretreated with the metal activator prior to addition of the xcex1-halo ester III, for example, iodine can be added to the metal and the mixture may be heated prior to addition of the (xcex1-halo ester III. Alternatively, the metal activator can be added simultaneously or after addition of the xcex1-halo ester III to the reaction mixture containing the metal. For example, 1,2-dibromoethane can be added to a mixture of the metal and the xcex1-halo ester III. Typically, the amount of metal activator added is from about 100 parts per million (ppm) to about 100,000 ppm relative to the xcex1-halo ester III. The use of a metal activator is particularly preferred when the reactive species generating reagent is magnesium metal.
The term xe2x80x9crate enhancerxe2x80x9d includes xe2x80x9cLewis acid rate enhancerxe2x80x9d and refers to a compound which increases the rate of intramolecular cyclization reaction of the reactive intermediate species, e.g., xcex1-magnesium halide ester. Exemplary Lewis acid rate enhancers which are useful in the present invention include magnesium metal; magnesium salts, such as magnesium bromide, magnesium chloride, magnesium iodide, magnesium acetate, and other organic and inorganic magnesium salt; alkyl aluminum compounds, such as trialkyl aluminum compounds (e.g., triethyl aluminum, tributyl aluminum, trimethyl aluminum); alkyl halide aluminum compounds, such as diethyl aluminum chloride, methyl aluminum dichloride; aluminum halides such as aluminum trichloride; and non-Lewis acid rate enhancers such as Reike magnesium, aluminum metal, cyclopentadiene, and anthracene. Preferably, the rate enhancer and is selected from the group consisting of zinc halides, iron halides, magnesium halides, trialkyl aluminum compounds, cyclopentadiene, anthracene, and mixtures thereof.
When Z in xcex1-halo ester III is an ester moiety (i.e., a moiety of the formula xe2x80x94C(xe2x95x90O)ORxe2x80x3), an alkoxide scavenger may be added to the reaction mixture to prevent the alkoxide which is formed in the reaction from interfering with the formation of the xcex4-lactone IA. Unless the context requires otherwise, the term xe2x80x9calkoxidexe2x80x9d refers to an alkoxide generated from the ester moiety of the Z group, i.e., xe2x80x94ORxe2x80x3 group of the moiety of the formula xe2x80x94C(xe2x95x90O)ORxe2x80x3. As used herein an xe2x80x9calkoxide scavengerxe2x80x9d refers to a compound which reacts with the alkoxide or the corresponding protonated hydroxy compound to form a relatively non-reactive compound or a moiety which physically traps the alkoxide or the corresponding protonated hydroxy compound, thereby preventing the alkoxide or the corresponding protonated hydroxy compound from interfering with the desired reaction. Exemplary alkoxide scavengers include silyl halides, such as trimethylsilyl chloride, t-butyldimethylsilyl chloride and other silyl halides which form silyl ethers with the alkoxide; metals such as aluminum, magnesium and other metals which form a relatively inert metal alkoxides; molecular sieves, which entrap the alkoxide within their physical structures; and other alkoxide deactivating compounds, such as activated basic alumina, deprotonated silica gel (e.g., from a reaction between silica gel and n-butyl lithium).
Processes of the present invention can also include the step of producing the xcex1-halo ester III which comprises contacting a (R)-xcex2-hydroxy compound of the formula: 
with an xcex1-halo activated carbonyl compound of the formula: 
in the presence of a base under conditions sufficient to produce the xcex1-halo ester III, where R1, R2, Y and Z are as described above, and X is a halide, preferably chloride or bromide (or Compound V may comprise a mixtures of chloride and bromide compounds), or C1-C10 carboxylate (i.e., xe2x80x94OC(xe2x95x90O)R, where R is H or C1-C9).
Reaction between xcex2-hydroxy compound IV and the xcex1-halo activated carbonyl compound V is typically conducted in an aprotic organic solvent such as hexane, ether, and those described above, preferably under an inert atmosphere. Exemplary bases which are useful in producing xcex1-halo ester III from xcex2-hydroxy compound IV and xcex1-halo activated carbonyl compound V include tertiary amines, such at triethylamine, tributylamine and dimethylaminopyridine (DMAP); pyridine; carbonates such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, and aqueous solutions of such bases; bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, and aqueous solutions of such bases; other relatively non-nucleophilic and mildly basic, i.e., having pKa of about 16 or less, and preferably pKa of about 10 or less, compounds. Other examples of reaction conditions for producing xcex1-halo ester III from xcex2-hydroxy compound IV and xcex1-halo activated carbonyl compound V are disclosed in the above mentioned U.S. Pat. Nos. 5,420,305 and 5,274,143, which are incorporated herein by reference in their entirety. The xcex1-halo ester III thus produced can be used directly without any further purification, or it can be purified, e.g., by distillation under reduced pressure, prior to its use.
The xcex1-halo activated carbonyl compound V can be readily prepared, for example, by halogenating the corresponding activated carbonyl compound (i.e., where Y is H) with xcex1-halogenating agent such as bromine. In one specific example, bromine is added to octanoyl chloride at temperature of about 55xc2x0 C., which resulted in formation of a mixture of xcex1-bromooctanoyl chloride and xcex1-bromooctanoyl bromide. This mixture can be used without further purification, as both of these compounds undergo a similar esterification reaction with the xcex2-hydroxy compound IV to produce the same corresponding xcex1-halo ester III.
The activated carbonyl compound in turn can be readily prepared from the corresponding carboxylic acid or esters by using a method known to one of ordinary skill in the art, including the use of anhydrides, or acyl halogenating agents. Exemplary acyl halogenating agents and general procedures for using the same are disclosed, for example, in xe2x80x9cComprehensive Organic Synthesis,xe2x80x9d vol. 6, Trost, Fleming and Winerfeldt eds., Pergamon Press, 1991, pp. 301-319, and xe2x80x9cThe Chemistry of Acyl Halides,xe2x80x9d Patai, ed., Interscience Publishers, 1972, pp. 35-64, which are incorporated herein by reference in their entirety.
Processes of the present invention can also include the step of enantioselectively producing the xcex2-hydroxy compound IV by an enantioselective reduction of a xcex2-keto compound of the formula: 
where R1 and Z are as described above.
In one particular embodiment of the present invention, where Z is a moiety of the formula xe2x80x94C(xe2x95x90O)W, especially where W is C1-C6 alkoxide, C6-C20 aryloxide or C7-C20 arylalkoxide, the xcex2-hydroxy compound IV is produced from a xcex2-ketoester of the formula: 
by hydrogenating the ketone carbonyl of the xcex2-ketoester VII in the presence of a chiral hydrogenation catalyst, where R1 is as described above and R10 is C1-C6 alkyl, C6-C20 aryl or C7-C20 arylalkyl. Preferably R10 is C1-C6 alkyl, more preferably methyl, or ethyl. The xe2x80x94OR10 moiety can be interchanged with other groups by a variety of methods known to one of ordinary skill in the art including by transesterification, amide formation, acyl halide formation, saponification and other methods which are disclosed in a variety of references including Advanced Organic Chemistry, 3rd ed., March, J., John Wiley and Sons, New York, N.Y., 1985, which is incorporated herein by reference in its entirety.
It should be appreciated that a non-chiral hydrogenation catalyst will result in racemic mixture of xcex2-hydroxy compound IV, and a chiral hydrogenation catalyst having an opposite configuration as those described below will result in xcex2-hydroxy compound having an opposite configuration as that shown in FIG. IV. One embodiment of the present invention provides a process for enantioselectively reducing the xcex2-ketoester VII using an enantiomerically enriched hydrogenation catalyst, i.e., hydrogenation catalyst having greater than about 97% enantiomeric excess (% ee).
In one particular embodiment of the present invention, the chiral hydrogenation catalyst comprises a ruthenium catalyst containing a chiral ligand such as those shown in the Examples section, including a catalyst of the formula: 
where each X2 is independently a halide, such as iodide, bromide or preferably chloride; or acetate; and each of R11 and R12 is independently H, C1-C6 alkyl or C1-C6 alkoxy, provided at least one of R11 or R12 is not H. Moreover, each phenyl group may contain more than one R11 or R12 groups. Furthermore, one or both of the phenyl groups of the biphenyl moiety may be replaced with other aromatic groups such as a naphthyl, pyridyl or other substituted aryl groups.
One of the useful hydrogenation catalyst of the present invention is a product produced by contacting a ruthenium diacetate of the formula Ru(OAc)2((R)-MeOBIPHEP) with a halide source, such as alkaline metal halides (e.g., LiX, NaX, KX and CsX, where X is a halide) or hydrohalides (e.g., HX, where X is a halide), preferably hydrochloric acid, where Ru(OAc)2((R)-MeOBIPHEP) is a compound of the formula: 
Without being bound by any theory, it is believed that treating Ru(OAc)2((R)xe2x80x94MeOBIPHEP) with hydrochloric acid results in replacing both of the OAc groups with chloride; thus, the resulting product is believed to be Ru(Cl)2((R)-MeOBIPHEP). Interestingly, however, when Ru(OAc)2((R)-MeOBIPHEP) is treated with less than about 2 equiv. of HCl, the resulting hydrogenation catalyst does not produce (R)-3-hydroxy compound IV in a high enantiomeric excess. Surprisingly and unexpectedly, in some cases such a chiral hydrogenation catalyst produces predominantly (S)-3-hydroxy compound. However, when at least about 5 equiv. of HCl is added to Ru(OAc)2((R)-MeOBIPHEP), preferably at least about 10 equiv. and more preferably at least about 20 equiv., the resulting chiral hydrogenation catalyst enantioselectively reduces the xcex2-ketoester VII to the corresponding (3R)-3-hydroxy compound IV.
The precursor of chiral hydrogenation catalyst of the present invention, i.e., ruthenium dicarboxylate diphosphine compound or [Ru(OC(xe2x95x90O)Rxe2x80x2)2(diphosphine)], can be prepared according the following reaction scheme: 
In this manner a variety of chiral ruthenium dicarboxylate diphosphine, including those listed in Example 16, can be prepared. The process for preparing a ruthenium dicarboxylate diphosphine compound generally involves contacting [RuCl2(COD)]n, which is commercially available or preferably prepared according to the procedure of Albers et al., Inorg. Synth., 1989, 26, 68, with a mixture of a carboxylate salt and the corresponding carboxylic acid, i.e., MOC(xe2x95x90O)Rxe2x80x2 and HOC(xe2x95x90O)Rxe2x80x2 mixture, such as sodium acetate/acetic acid and sodium pivalate/pivalic acid mixtures, in an aprotic organic solvent, preferably toluene. The mixture is heated at a temperature of about 80xc2x0 C. to about 120xc2x0 C., preferably about 100xc2x0 C. A typical reaction time is from about 15 hours to about 72 hours, preferably from about 20 hours to about 48 hours. The amount of carboxylate salt used can be about 2 equiv. to about 50 equiv., preferably about 2 equiv. to about 25 equiv., more preferably about 2.1 equiv. to about 10 equiv., and most preferably about 2.5 equiv. Preferably a small excess of [RuCl2(COD)]n is used relative to the diphosphine compound to ensure complete conversion of the diphosphine compound.
While commercially available [RuCl2(COD)]n complex can be used, it has been found that freshly prepared [RuCl2(COD)]n complex from ruthenium trichloride generally affords shorter reaction time, more consistent and/or higher yield of ruthenium dicarboxylate diphosphine compound. In this manner, a one-pot synthesis of ruthenium dicarboxylate diphosphine compound can be achieved from inexpensive and readily available ruthenium trichloride.
The xcex2-hydroxy compound (e.g., (3R)-3-hydroxy compound) IV can be further purified, i.e., enantiomerically enriched, by recrystallizing the initial product to afford a product having at least about 99% ee. Therefore, it should be appreciated that depending on the cost of a particular chiral hydrogenation catalyst, it may be more economical to use a chiral hydrogenation catalyst which provides less than about 95% ee of the xcex2-hydroxy compound IV, which can be further enantiomerically enriched by recrystallization.
Unlike currently used ruthenium-based hydrogenation catalysts for asymmetric reduction of methyl 3-oxotetradecano-late, the hydrogenation catalyst of the present invention does not require high purity conditions, e.g., hydrogen gas having purity of at least about 99.99%, to produce methyl 3-hydroxytetradecanoate in high yield and high enantiomeric excess. In fact, the asymmetric hydrogenation of methyl 3-oxotetradecanoate under technical grade conditions, e.g., hydrogen gas having purity of about 99.5% and nitrogen gas having purity of about 99.5%, using the hydrogenation catalyst of the present invention proceeds with a substantially similar rate as those requiring high purity reaction conditions. Moreover, the hydrogenation catalyst of the present invention allows the use of lower hydrogen gas pressure, thereby reducing the cost of initial capital investments and reducing the potential danger associated with high pressure hydrogen gas reaction conditions. In addition, by using asymmetric hydrogenation processes described above, the present invention allows asymmetric synthesis of the xcex4-lactone I without a need for resolving any racemic intermediates.
Typically, hydrogenation of xcex2-ketoester VII, e.g., methyl 3-oxotetradecanoate, is conducted in a conventional hydrogenation solvent including an alkyl alcohol, such as ethanol or preferably in methanol, at a reaction temperature of about 80xc2x0 C. The concentration of the substrate (i.e., xcex2-ketoester VII) in hydrogenation reaction is generally at about 40 wt %, and the ratio of HCl to Ru(OAc)2((R)-MeOBIPHEP) in the hydrogenation catalyst is about 20:1. A typical ratio of methyl 3-oxotetradecanoate to the hydrogenation catalyst is from about 5000:1 to about 50,000:1. To this reaction mixture, typically from about 40 bars to about 80 bars of technical grade hydrogen gas is added, and the reaction is allowed to proceed for about 4 hours (h).
In this manner, the xcex2-hydroxy compound IV, such as methyl (R)-3-hydroxy tetradecanoate, can be produced in at least about 90% isolated yield from the corresponding xcex2-ketoester VII, more preferably in at least about 93% isolated yield and most preferably in at least about 95% isolated yield. The enantiomeric excess of xcex2-hydroxy compound IV produced is at least about 90% ee, preferably at least about 95% ee, and more preferably at least about 99% ee. The enantiomeric excess can be increased to at least about 95% ee after a single recrystallization, preferably at least about 99% ee, and most preferably at least about 99.5% ee.
The xcex2-ketoester VII can be readily prepared by a variety of known methods. See for example, Viscontini et al., Helv. Chim. Acta, 1952, 284, 2280-2282, Case-Green, Synlett, 1991, 781-782, and U.S. Pat. No. 5,945,559, issued to Sotoguchi et al., which are incorporated herein by reference in their entirety. However, the present inventors have found that the xcex2-ketoester VII, in particular where R1 is undecyl, can be readily obtained in high yield, preferably at least about 85% yield, by the following process. Addition of alkyl acetoacetate, e.g., methyl acetoacetate, to a non-polar solution of magnesium alkoxide, e.g., magnesium methoxide in toluene, and heating the mixture to at least about 100xc2x0 C. with removal of any alkyl alcohol that is generated, e.g., from protonation of magnesium alkoxide, produces magnesium salt of alkyl acetoacetate. Addition of an acyl chloride compound, e.g., lauroyl chloride, to the resulting alkyl acetoacetate magnesium salt at about 60xc2x0 C. produces a tri-carbonyl compound. Heating the tri-carbonyl compound, preferably to at least about 70xc2x0 C., in the presence of an alcohol, preferably methanol, provides the xcex2-ketoester VII in at least about 80% yield, preferably at least about 85% yield.